Serious acute and chronic pains are nociception and pains caused by introducing excitement of nociceptor due to various damage stimuli into central nervous system through impulse of transporter of nociceptive information. Serious acute and chronic pains include tumor pain, postoperative pain, and various recurrent acute and chronic pains, which perplex millions of patents, and are a major clinical problem currently.
The use of the existing opioid antalgic agents is limited due to drug addiction and side effects of respiratory depression, gastric motility reduction, etc. Therefore, to find central antalgic drugs that not only maintain a strong antalgic effect but also overcome the above defects and can be clinically applied safely is the main target in the antalgic field and studies on novel drugs. Although tremendous effects have been made on chemical and biological field during the last ten years, not any big progresses are made yet. Studies on novel central antalgic drugs have become the focus of the field. Large pharmaceutical companies such as Pfizer and Merck have invested huge capitals in the development of a novel non-addictive central antalgic agent.
Currently used non-opioid antalgics mainly include, based on the action mechanisms, NMDA receptor antagonist (such as ketamine), 5-HT reuptake inhibitor (such as tramadol), potassium channel opener (such as flupirtine), cyclooxygenase 2 inhibitors (such as celecoxib), calcium channel antagonist (such as Ziconotide), etc. These drugs improve the drug addiction and side effects compared with previous drugs to some extent, as specifically introduced in, for example, U.S. Pat. No. 6,339,105, U.S. Pat. No. 4,481,205, U.S. Pat. No. 5,760,068, U.S. Pat. No. 5,189,020, yet still have different degree of drug addiction or large toxic side effects. For example, ketamine, tramadol and flupirtine still cause addiction; celecoxib has potential side effects one cardiovascular; ziconotide may cause orthostatic hypotension easily, etc. In addition, effects of currently existing drugs are far from the requirements of control of pain of different clinical patients, in particular for some cancer pain, serious chronic pain and some neuropathic pain. There are no appropriate, safe and effective antalgic drugs. Therefore, there is a continuous need to develop non-addictive antalgic drugs having novel chemical structure, less toxic side effect, and being widely applicable and clinically safe to meet requirements of different patients suffering from pains. Further, market demand for non-opioid antalgic drugs is tremendous. A novel antalgic drug will generate great social and economic benefits.
The present inventor discloses an aralkyl-ketone piperazine derivative and use of the derivative as a novel antalgic and sedative drug in the application for Chinese patent for invention of the No. CN1381449 in 2002, wherein the compound has a non-addictive central antalgic effect. The aralkyl piperidine derivative of the present invention is a novel compound not disclosed, which has different chemical structure, even less toxic side effects and higher safety compared with the above application for patent.